1. Field of the Invention
The present invention relates to crystals of alanine alkyl ester sulfonates, which exhibit low hygroscopicity and low corrosiveness, and which are useful as intermediates for the production of pharmaceutical compounds having an alanine skeleton or as an alanine-containing peptide synthetic reagent. The present invention also relates to methods of producing such a crystal of an alanine alkyl ester sulfonate.
2. Discussion of the Background
Alanine lower alkyl ester compounds are useful as intermediates for the production of pharmaceutical compounds having an alanine skeleton or as alanine-containing peptide synthetic reagents. Generally, alanine lower alkyl esters are distributed in the form of a hydrochloride salt, and, for example, alanine methyl ester hydrochloride (hereinafter sometimes to be abbreviated as “Ala-OMe HCl salt”), alanine ethyl ester hydrochloride (hereinafter sometimes to be abbreviated as “Ala-OEt HCl salt”), and the like are commercially available. However, these hydrochlorides are hygroscopic and highly deliquescent, which makes handling thereof difficult. In addition, due to moisture absorption and deliquescence, the ester moiety such as alanine methyl ester (hereinafter sometimes to be abbreviated as “Ala-OMe”), alanine ethyl ester (hereinafter sometimes to be abbreviated as “Ala-OEt”) and the like is hydrolyzed into methanol, ethanol and the like, and the purity becomes low. Particularly, when a synthetic reaction is carried out using such a compound, the alanine resulting from the decomposition reacts to produce a substance other than the desired product. Therefore, an extremely serious problem occurs when such compounds are used as starting materials for a pharmaceutical product required to have high purity.
As a substance other than hydrochloride, alanine ethyl ester hydrobromide, alanine ethyl ester p-toluenesulfonate (4-methylbenzenesulfonate) and the like are known. However, hydrohalides such as hydrochloride, hydrobromide, and the like exhibit a high corrosiveness to metals, and an industrial process using such a compound requires the use of equipment having a high resistance to corrosion.
In the case of p-toluenesulfonate, Kato et al. (Nippon Kagaku Kaishi, vol. 83, p. 1151 (1962)) obtained various amino acid ethyl ester p-toluenesulfonates as crystals by a method comprising an azeotropic dehydration treatment of p-toluenesulfonic acid and various amino acids in ethanol in the presence of carbon tetrachloride to effect esterification. However, Kato et al. reported that alanine ethyl ester p-toluenesulfonate became oily and failed to crystallize. On the other hand, DJ. Collins et al. (Aust. J. Chem., 1999, vol. 52, pp. 379–385) reported that they obtained a crystal of alanine ethyl ester p-toluenesulfonate by transesterification using ethyl p-toluenesulfonate. However, when the present inventors tried to obtain L-alanine ethyl ester p-toluenesulfonate by transesterification, the reaction took a considerably long time and this method was found to be not entirely sufficient as an industrial production method.
Thus, there remains a need for crystals of alanine lower alkyl esters salts. There also remains a need for crystals of alanine lower alkyl esters salts, which exhibit reduced hygroscopicity. There also remains a need for crystals of alanine lower alkyl esters salts, which exhibit reduced corrosiveness. There also remains a need for a method for conveniently preparing such crystals.